Dialysis therapy has been established as a treatment for patients with renal insufficiency, and performed for the purpose of controlling the concentration of blood electrolyte components, removal of uremic substances, correction of acid-base balance, or the like. The dialysis fluid used in the dialysis treatment includes a plurality of components, which should be combined at appropriate concentrations so as to satisfy objectives of treatment with less strain on the living body.
In recent years, bicarbonate dialysis fluids formed with use of sodium hydrogen carbonate for the correction of acid-base balance are popular, and it is also essential to combine an acid to make the dialysis fluid neutral. If these are distributed in the same container in which they coexist, such components generate carbon dioxide gas in the container and become very unstable, because of which, in general, two agents of agent A and agent B are produced as a dialysis agent to be mixed at the time of use for the preparation of the dialysis fluid.
Usually, the agent A contains sodium chloride, potassium chloride, calcium chloride, magnesium chloride, pH adjusting agent (acid and buffer ingredients as optional ingredients), and glucose, and the agent B contains sodium hydrogen carbonate. Moreover, in order to prevent the precipitation of insoluble salts, the formulation of calcium chloride and magnesium chloride into the agent B is contraindicated.
Conventionally, these agents A and B have been used as a liquid filled in a polyethylene container, but problems have arisen concerning transportation costs and poor operability in hospitals (weight, storage space, and disposal method of polyethylene container). As a result, today, a dialysis agent in powder form to be mixed with water before use has been put into practical use.
Although original dialysis agents in powder form are comprised of three agents including an agent A-1 containing a pH adjusting agent and an electrolyte, an A-2 agent consisting of only glucose, and an agent B consisting of sodium hydrogen carbonate, currently the two-pack type dialysis agents consisting of the agent A and the agent B are popular where the agent A-1 and the agent A-2 are combined.
Today, the bicarbonate dialysis agent is formulated so as to have the following composition and concentration when clinically used as a dialysis fluid.
TABLE 1Na+130~150mEq/LK+0~3.0mEq/LCa2+2.0~4.0mEq/LMg2+0~2.0mEq/LCl−90~120mEq/LHCO3−20~40mEq/LAcetic acid0~12mEq/LCitric acid0~3mEq/LGlucose0~250mg/dL
At the time of dialysis treatment, a liquid type agent A, or the agent A obtained by dissolving a powder type agent A, or the agent A obtained by dissolving powder type agents A-1 and A-2, and a liquid type agent B or the agent B obtained by dissolving a powder type agent B are diluted and mixed to be used as the dialysis fluid. However, as mentioned above, the bicarbonate dialysis fluid generates carbon dioxide gas as a result of coexistence of an acid and sodium hydrogen carbonate over time and the pH rises at the same time, so that an insoluble calcium carbonate and the like may be generated. This phenomenon raises such a problem that calcium concentration effective in the treatment is reduced and crystals are adhered to the tube or hose of the dialysis machine.
On the other hand, acetic acid has been used for a long time as a pH adjusting agent, but, in recent years, peripheral vasodilator action and cardiac inhibitory effect, induction of inflammatory cytokines, and strain on the patient with acetate intolerance, due to acetic acid have been questioned. That is, although acetic acid is metabolized in a short time and is not accumulated in the living body, it has a cardiac inhibitory effect, a peripheral vasodilator action, and, as a result, an action of reducing blood pressure. Since dialysis treatment is also a treatment for the removal of moisture in the body, a reduction in blood pressure due to moisture removal during and after dialysis would inevitably occur. The symptomatic treatment such as control of moisture removal and administration of vasopressors is often used in combination to prevent the reduction in blood pressure. The presence or absence of symptoms caused by these effects are different for each patient, and thus it is thought that such symptoms may also be attributed to the concentration of acetic acid contained in the dialysis fluid. In recent years, a dialysis method without acetic acid (an acetate free dialysis method) as one approach to overcome such a situation has been proposed.
Therefore, nowadays, those obtained by formulating citric acid in place of acetic acid as a pH adjusting agent are commercially available and have been clinically used (for example, see Patent Documents 1 to 4). However, there has been raised such a problem that because citric acid has a strong chelating action, a portion of the calcium in the dialysis fluid is chelated, thereby to decrease the ionized calcium concentration, and because citric acid is a stronger acid than acetic acid, the pH of the concentrated solution A lowers to cause a risk of corrosion of parts of a dissolution apparatus or a dialysis machine. If a large amount of organic acid salts are formulated in order to increase the pH of the solution A, crystals of calcium citrate are precipitated to affect the composition, which is also a problem. In other words, since citric acid is easy to form a chelate with an alkaline earth metal, it forms a chelate with calcium and magnesium in the dialysis fluid component. This action has a great effect on calcium in particular, and since control of the amount of calcium is very important in dialysis treatment, there is a drawback such that decrease of ionized calcium concentration due to such a chelate significantly affects the calcium balance in patients. For example, if the calcium and citric acid were included at almost the same concentration (ion equivalent ratio) in the dialysis fluid, about 35% of calcium is chelated to reduce the ionized calcium concentration in the dialysis fluid by a corresponding amount, resulting in a difficulty to control the blood calcium level. In addition, since citric acid also enters the body by dialysis, there is a risk such that citric acid binds to calcium in the blood to generate a poorly soluble calcium citrate, which is then deposited in the blood vessel. In addition, there is a concern such that it becomes difficult to control the calcium in the body, which is important for dialysis patients, because there is no explicit dynamics of the components such as citric acid and calcium after they enter the blood at the same time. Furthermore, there is a problem in the following points in that the decrease in ionized calcium concentration due to citric acid promotes the relaxation of cardiac muscle and vascular smooth muscle, leading to low blood pressure, and that citric acid is difficult to use in patients with bleeding tendency because it has an anticoagulant effect.
Further, citric acid is easy to handle in the normal handling because it is a solid, but since its concentrate is strongly acidic, hydrogen chloride gas is easily generated upon partial moisture absorption even if it is stored in powder form, which may cause a partial metal corrosion of the dissolution apparatus, resin deterioration, and the like. For example, Patent Document 1 describes a powder-type dialysis agent free from acetic acid, said dialysis agent being able to prevent the formation of insoluble compounds, suppress the precipitation of calcium carbonate, and inhibit the degradation of glucose by using a citric acid. These effects can be achieved by using citric acid within a limited range of pH 2.2 to 2.9. With such a pH range, there is a risk of corrosion of the dissolution apparatus and the dialysis machine, and the decrease in the ionized calcium concentration due to the strong chelation effect of citric acid may also affect the therapeutic effect as described above.
Therefore, it is not optimal to use citric acid as an acid other than acetic acid. Although organic acids other than citric acid which are safe for the living body, such as malic acid, lactic acid, fumaric acid, gluconic acid, etc. could be used, it is not clear about their behavior in the body after dialysis in chronic use and thus the amount of these acids should be reduced as much as possible, and it is also important to take into account the influence of these acid components on the dialysis fluid preparation apparatus and the dialysis machine.
On the other hand, as described above, it is concerned that citric acid etc. would decrease the ionized calcium concentration due to its strong chelating action, but, strictly speaking, acetic acid also reduces the ionized calcium concentration. The clinical problem of acetic acid has been neglected probably because acetic acid is metabolized fast, but, in practice, a dialysis fluid formed with use of acetic acid has a lower ionized calcium concentration than a dialysis fluid formed with use of hydrochloric acid as the pH adjusting agent, and the ionized calcium concentration is further reduced as the content of acetic acid is increased. Although not known in general, it is certain that a large content of acetic acid is a factor in lowering the ionized calcium concentration, but not as much as citric acid. From this point, it is clear that a less content of acetic acid is desirable.
All the dialysis agents A containing acetic acid which have been sold in Japan in the past have a total acetic acid content of 8 mEq/L or higher and a ratio of sodium acetate to acetic acid of 2.2 or more, regardless of whether the dialysis agent A is a liquid or a solid. Since the pH of the liquid A is 4.6 or more under this condition, there is such an advantage that the dialysis fluid preparation apparatus is less likely to be corroded and the dialysis fluid is easy to handle, in view of production of the liquid formulation.
The reason of the formulation of 8 mEq/L or higher of the total acetate content in Japan is because the past acetate dialysis agent (in which sodium acetate is formulated in 30 mEq/L or higher without using sodium bicarbonate) is changed to the bicarbonate dialysis agent so that benefits of bicarbonate and benefits of acetate can be brought about in combination, i.e., blood bicarbonate ions can be directly corrected whereas bicarbonate ions can be slowly corrected through the acetate metabolism.
On the other hand, liquid preparations (liquid A) are sold primarily outside of Japan. Sodium acetate is used as a part of the alkalizing agent in Japan, whereas only sodium hydrogen carbonate of the agent B is used as the alkalizing agent outside of Japan and sodium acetate is not used. Therefore, as an acetate ingredient, only acetic acid in an amount of 4 mEq/L or less has been used mainly as a pH adjusting agent.
However, when sodium acetate is not included in the dialysis liquid as described above, the pH of liquid A is 3 or less, resulting in adverse effects such as corrosion of the metal member of the dialysis fluid preparation apparatus and the dialysis machine, and strong irritation to the skin. In late years, a liquid A (including those prepared by dissolving an agent A powder) having a pH of 3 or less has been commercially available and the dialysis fluid preparation equipment manufacturers also deal with such a liquid A by employing parts made of acid resistant materials strongly resistant to corrosion. However, these materials are economically unfavorable because they are expensive.
In addition, the dialysis fluid containing acetic acid has a very strong and uncomfortable odor of acetic acid and thus, in the dialysis facilities where large quantities of dialysis fluid are handled, it is necessary to care the dialysis agent not to be placed in an open system as much as possible during its manufacturing or handling even though it is a liquid.
Next, in Japan, powder formulations of dialysis agents are popular as a result of a trend toward powdering of dialysis agents, and a large number of patents relating to bicarbonate dialysis agents that can be used in powder form have been disclosed. For example, Patent Document 5 describes that the manufacturing of the powder preparation becomes easier, when sodium acetate is combined to acetic acid in a ratio (molar ratio) of 1.56 to 3.29, preferably 2.49 to 3.29, in a powdery dialysis agent A because sodium acetate easily adsorbs acetic acid and is difficult to volatilize. However, even in the technique disclosed in Patent Document 5, the total acetate ion concentration of the finally prepared dialysis fluid is assumed to be 8 mEq/L or higher.
In addition, it is typical that sodium acetate is combined in an amount of from more than two times to five times, relative to acetic acid, and, for example, combination ratio of sodium acetate is 2.2 times (acetic acid 2.5 mEq/L:sodium acetate 5.5 mEq/L) for commercially available LYMPACK TA-1 in Japan, three times (acetic acid 2 mEq/L:sodium acetate 6 mEq/L) for KINDALY 2E, 4.5 times (acetic acid 2 mEq/L:sodium acetate 9 mEq/L) for HI-SOLV F, and 5 times (acetic acid 2 mEq/L: sodium acetate 10 mEq/L) for HI-SOLV D. Even apart from the transition of formulation in the past, the reason why the ratio of two times or less of sodium acetate to acetic acid has not yet been disclosed is because of a problem with acetic acid odor. In other words, as the ratio of sodium acetate is increased to three times, four times and so on, the acetic acid odor in powder preparation is reduced. In contrast, as the ratio of sodium acetate relative to acetic acid becomes close to double or becomes double or less, an excruciating odor of acetic acid occurs, because of which its practical use is not possible.
As seen from the above, even in Japan and abroad, there are only dialysis fluids containing acetic acid and having a total acetate ion concentration of 4 mEq/L or less, or 8 mEq/L or higher, and there has been no dialysis agent put to practical use, wherein the pH of the liquid A (concentrate) obtained by dissolving a solid agent A in water is set to about 4 and the total acetate ion concentration in the dialysis fluid is set to 4 to 8 mEq/L.
Only Patent Document 6 discloses that a preferable total acetate ion concentration is up to 5 mEq/L in the dialysis fluid containing acetic acid and sodium acetate. However, Patent Document 6 discloses a primary concentrate (sodium hydrogen carbonate, sodium chloride, and sodium acetate) and an individual concentrate (sodium, potassium, calcium, magnesium, hydrochloric acid/or acetic acid, glucose), and describes that the molar ratio of acetate/sodium in the final dialysis fluid obtained by combining the primary concentrate with the individual concentrate is 0.03 or less. That is, if the sodium content in the dialysis fluid is set to 140 mEq/L as typical cases, the total content of acetate ions in the dialysis fluid corresponds to 4.2 mEq/L or less. Further, Patent Document 6 describes that the sodium acetate to be combined with the primary concentrate is in an acetate/sodium ratio of less than 0.03, which indicates that the acetate ion content in the dialysis fluid is less than about 4 mEq/L. That is, Patent Document 6 discloses the embodiment of only a dialysis agent useful in the production of a dialysis fluid having a total acetate ion concentration of less than about 4 mEq/L.
In addition, according to Patent Document 6, the dialysis agent of Patent Document 6 enables individual patients to select various individual concentrates that can be provided, and the object of combining sodium acetate is to improve the stability and preserving property of the primary concentrate at low temperatures. In other words, a small amount of sodium acetate in the primary concentrate increases the solubility of sodium hydrogen carbonate and suppresses the formation of precipitates.
That is, since the dialysis agent of Patent Document 6 enables to perform the dialysis with various formulations according to the individual patients (calcium, magnesium, potassium, etc.) and requires a fairly complex system so that acetic acid and acetate salt are designed to be combined into different preparations, it differs from a general two-pack type dialysis agent comprising agent A and agent B in its dosage form and preparation method of the dialysis fluid. In addition, the technical means for reducing the acetic acid odor in the dialysis agent has not been studied at all in Patent Document 6. Further, in the dialysis agent of Patent Document 6, since the individual concentrate includes hydrochloric acid or acetic acid and does not include a basic ingredient, so that it will be exposed to a strong acidic condition of pH 3 or less, the dialysis agent of Patent Document 6 is not necessarily a good preparation in regard to corrosion problems of the dialysis fluid manufacturing apparatus, stability of glucose, and the like.
As described above, among general two-pack type dialysis agents that are widely used and contain the agent A (electrolytes, acids, glucose, etc.) and the agent B (sodium hydrogen carbonate) in combination, a dialysis agent having a total acetate ion concentration of 4 to 8 mEq/L does not exist, let alone any practical dialysis agent in powder form due to its strong acetic acid odor.
In fact, domestically and abroad, there is no successful example of any actual commercialization of dialysis agents in powder form, wherein the total acetate ion concentration has been set to less than 8 mEq/L in the dialysis fluid. This is probably because dialysis agents in powder form are difficult to commercialize as such dialysis agents poorly withstand clinical use in terms of fluidity and stability, and acetic acid odor. For example, acetic acid has a big influence on environment due to its pungent odor. Clinical dialysis fluid preparation is generally performed by a clinical engineer, but there is a problem of discomfort associated with pungent odor. Further, since acetic acid is also a factor in glucose degradation, a dialysis agent that is formulated with use of acetic acid and contains glucose is required to be formulated in sufficient consideration of the stability of glucose. Therefore, it is necessary to find the optimal formulation while sufficiently considering such problems.
In recent years, it has been reported at conferences and the like that a lower content of total acetate ion in a dialysis fluid is physiologically desirable and the total acetate ion are preferably less than 6 mEq/L or less than 4 mEq/L. Thus, there is an increasing demand for development of a dialysis agent that can be set to a lower total acetate ion concentration. It is believed that, by suppressing the total acetate ion concentration within a low range as described above, the onset of symptoms such as decrease in blood pressure can be suppressed almost without raising blood acetic acid concentration of the patient during dialysis, thereby to significantly improve safety, because the metabolic rate of acetic acid is faster than that of other organic acids and the content of acetic acid is less than that of conventional products. However, since a dialysis fluid having a low level of total acetate ion concentration, reported in the academic conferences, etc., is prepared by simply halving the amount of each of acetic acid and sodium acetate of the dialysis agent A that is set to the total acetate ion concentration of 8 mEq/L, there is a disadvantage that the pH of the dialysis fluid is inevitably high. In such a dialysis fluid with a high pH, its continuous use potentially causes vascular calcification of the patient, and there is also a problem of calcium deposition in the dialysis fluid preparation apparatus and the dialysis machine.
On the other hand, as a method for reducing the acetic acid odor as described above, there is disclosed a method of reducing the generated acetic acid odor by adding or spraying acetic acid to sodium acetate so that the acetic acid is adsorbed on the sodium acetate. There is also disclosed a method of mixing, as the dialysis component, sodium diacetate prepared in the same manner, or a method of forming sodium diacetate on the surface of the electrolyte component by adding acetic acid to an electrolyte component coated with sodium acetate (Patent Documents 5, 7 to 9). However, in any of these methods, sodium acetate relative to acetic acid is contained in an equivalent ratio of more than 2, and there is no description of the case with an equivalent ratio of 2 or less. Further, in these methods, labor in manufacturing, such as necessity for drying process under acetic acid atmosphere, is concerned. In addition, Patent Documents 8 and 9 disclose that sodium acetate is used in an equimolar or higher ratio to acetic acid, but a specific method in the case of using an equimolar amount of sodium acetate has not been described. In such a method, the condition of the equivalent ratio of substantially 3 or more, which is less likely to volatilize the acetic acid, is adopted. Moreover, even in these Patent Documents, the total acetate ion content in the dialysis fluid is not designed to be 4 to 8 mEq/L and these methods therein are not intended to disclose a formulation technique applicable to a low-acetate dialysis agent.
Based on the background of such a prior art, the development of a dialysis agent which allows for a low total acetate ion content in the dialysis fluid, exhibits excellent storage stability of glucose or the like and a reduced acetic acid odor, can suppress the corrosion of the dialysis fluid preparation apparatus and the dialysis machine, and can be put into practical use, as well as the development of a production method thereof has been desired.